Zaleplon possesses anxiolytic, antiepileptic, sedative and hypnotic properties. It is approved by the U.S. Food and Drug Administration for short-term treatment of insomnia and is available by prescription under the brand name Sonata®. The molecular structure of zaleplon is known and may be represented as:

The IUPAC name of zaleplon is N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide.
U.S. Pat. No. 4,626,538 (“the '538 patent”) provides a general methodology for preparing zaleplon and structurally related compounds. In Example 2 of the '538 patent, N-(3-acetylphenyl)ethanamide 1 is reacted with dimethylformamide dimethyl acetal to form N-[3-[3-(dimethylamino)-1-oxo-2-propenyl)]phenyl]-N-acetamide 2. In Example 7 of the '538 patent, the primary amide of acetamide 2 is alkylated with ethyl iodide, forming N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide 3. Zaleplon was prepared in Example 14 by condensing ethylacetamide 3 and 3-amino-4-cyanopyrazole 4 in refluxing glacial acetic acid. Zaleplon was worked up by partitioning the non-volatiles between saturated sodium bicarbonate and dichloromethane, drying the organic phase, passing the organic phase through an adsorbent (magnesium silicate), adding hexane to the organic phase, cooling the organic phase and collecting a solid that forms in the organic phase. The product is reported to have a melting point of 186-187° C. The overall synthesis is depicted in Scheme 1. The '538 patent does not indicate that byproducts were formed in any of the reactions or explain how byproducts could be separated from zaleplon if they did form.

U.S. Pat. No. 5,714,607 (“the '607 patent”) describes an improved process for preparing zaleplon. According to the '607 patent, zaleplon can be obtained in improved yield and purity if the final step of the '538 patent process is modified by adding water to the acetic acid solvent at about 10% to about 85% (v/v). As stated in the '607 patent, the improved conditions shorten the reaction time from about 3-3.5 h to about 1-3.5 hours. According to Table 1 of the '607 patent, zaleplon was obtained in yields ranging from 81.7-90% and in HPLC purity ranging from 98.77 to 99.4%. In each of the examples, zaleplon was obtained by crystallization out of the reaction mixtures, which were mixtures of water and acetic acid. The '538 patent does not indicate that byproducts were formed in the process or explain how byproducts could be separated from zaleplon if they were to form.
Commonly assigned co-pending U.S. patent application Ser. No. 10/170,673 discloses a process for preparing zaleplon by condensing N-ethylacetamide 3 and pyrazole 4 or their acid addition salts in a reaction medium comprising water and a water-miscible organic compound.
U.S. patent application Ser. No. 10/170,673, filed Jun. 12, 2002, is hereby incorporated by reference in its entirety.
In order to obtain marketing approval for a new drug product, manufacturers have to submit to the regulatory authorities evidence to show that the product is acceptable for human administration. Such a submission must include, among other things, analytical data to show the impurity profile of the product to demonstrate that the impurities are absent, or are present only a negligible amount. For such a demonstration there is a need for analytical methods capable of detection of the impurities and reference standards for identification and assaying thereof. There is also a need for reference standards in such analytical methods.
The U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER) has promulgated guidelines recommending that new drug and generic drug applicants identify organic impurities of 0.1% or greater in the active ingredient. “Guideline on Impurities in New Drug Substances” 61 Fed. Reg. 371 (1996), “Guidance for Industry ANDAs: Impurities in Drug Substances” 64 Fed. Reg. 67917 (1999). Unless an impurity is a human metabolite, has been tested for safety, or was present in a composition that was shown to be safe in clinical trials, the CDER further recommends that the drug applicant reduce the amount of the impurity in the active ingredient to below 0.1%. Thus, there is a need to isolate impurities in drug substances so that their pharmacology and toxicology can be studied.
Crystalline forms, that include polymorphs and pseudopolymorphs, are distinct solids sharing the same structural formula, yet having different physical properties due to different conformations and/or orientations of the molecule in the unit cell. One physical property that can vary between crystalline forms is solubility, which can affect the drug's bioavailability. Crystalline forms of a compound can be differentiated in a laboratory by powder X-ray diffraction spectroscopy. For a general review of crystalline forms (i.e. polymorphs and pseudopolymorphs) and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975).
The discovery of new crystalline forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. The present invention provides four new crystalline forms of zaleplon.